Functionalizations of oxindoles and thio-oxindoles under metal-free conditions

Abstract

This thesis aims to modify oxindoles and thio-oxindoles, which are important scaffolds with biological significance, in order to enhance their functional properties. Chapter-1: Introduction The text discusses alkaloids, which are naturally occurring organic molecules produced by plants for self-protection against pathogens and herbivores. It focuses on oxindole, an alkaloid derived from the Cat’s Claw plant, which has traditionally been used in medicine for treating various diseases and infections. The chapter explores the diverse biological effects of these compounds and their correlation with the position of substituents on oxindole. It also delves into the development of methods for constructing oxindoles and different protocols for their functionalization. Additionally, it highlights the synthesis and biological activities of thio-oxindoles, emphasizing their growing importance in constructing indole-fused and spiro organosulfur compounds. Chapter-2 In this study, we have disclosed N-alkylation and C-alkylation reactions of 2-oxindoles and S-alkylation of thio-oxindoles with secondary alcohols. Interestingly, these chemoselective reactions are tunable by changing the reaction conditions. Utilization of protic solvent and Brønsted acid catalyst afforded C-alkylation, whereas, aprotic solvent and Lewis acid catalyst afforded N-alkylation of 2-oxindoles in good to excellent yields. Regioselectivity is achieved by protecting the N-centre of the oxindole and C5 alkylated product is furnished exclusively. This protocol is notable because it demonstrates functionalization at the C7 position of oxindole without the need for any directing group at the N-centre. Further, a new protocol has been reported for C-H oxygenation at the benzylic position of one of the C5 alkylated derivative. Chapter 3: Fluorine-containing moieties are of great interest in the development of new synthetic methods due to their considerable medicinal value. In this regard, researchers have explored the direct trifluoroethylation using CF3CH2-containing precursors, however, the high cost, prolonged synthesis time, toxic nature, and instability towards transition metal catalysis of these precursors have proven to be a challenge. As an alternative, generating trifluoroethylation by in situ production of 2,2,2-trifluorodiazoethane (CF3CHN2) from CF3CH2NH2·HCl in solution is comparatively easy, safe, and a greener approach. But, previous reports using 2,2,2-trifluorodiazoethane in solution also demonstrate the use of transition metal-catalyzed pathways under harsh reaction conditions and hazardous solvents. Herein, we have developed a triflic acid (commercially available and cheap Brønsted acid) catalyzed protocol for O-trifluoroethylation of 3,3-disubstituted, monosubstituted, unsubstituted, chalcone-based oxindoles, isoindolines, and S-trifluoroethylation of thio-oxindoles in the presence of in situ generated 2,2,2-trifluorodiazoethane in solution. This highly efficient metal- and additive-free strategy offers a mild and feasible approach to access chemoselective trifluoroethylation in good to excellent yields in a very short reaction time (10 minutes). This methodology exhibits a wide range of substrate scope, rendering it a versatile approach that can be effectively employed for all types of cyclic amides. Additionally, the method is scalable for larger operations. The calculation of various green chemistry metrics, such as high atom economy (93%), carbon efficiency (100%), reaction mass efficiency (74%), and lower E-factor (0.40 kg waste/ 1kg product) confirms the eco-friendliness of this approach. The EcoScale evaluation showcases the simplicity, effectiveness, and eco-friendliness of this approach. Chapter 4: This research has led to a significant advancement in the field of organic synthesis. We have successfully developed a method to directly fluorinate the C7-H position of oxindoles, N-hydroxymethylate oxindole, form dithianes, and transform thio-oxindole to oxindole. This breakthrough was the result of thorough experimentation involving the testing of various solvents, bases, and reaction temperatures. A key element in this process is the dual role played by selectfluor, acting as both an oxidant and a fluorine source. Our innovative protocol offers a practical and efficient approach to synthesizing oxindole analogs under mild conditions, resulting in good to excellent yields of the desired products. Significantly, our method demonstrates exceptional regioselectivity, high tolerance to functional groups, and is free of additives, making it an enticing option for researchers and practitioners in organic synthesis and pharmaceutical chemistry. Chapter 5. In this chapter, I provide a detailed overview of the work that has been accomplished in the thesis entitled as “Functionalizations of Oxindoles and Thio-oxindoles Under Metal-Free Conditions”.